title: High-dose glucocorticoid aggravates TBI-associated corticosteroid insufficiency by inducing hypothalamic neuronal apoptosis.
abstract: Emerging experimental and clinical data suggest that severe illness, such as traumatic brain injury (TBI), can induce critical illness-related corticosteroid insufficiency (CIRCI). However, underlying mechanisms of this TBI-associated CIRCI remain poorly understood. We hypothesized that dexamethasone (DXM), a synthetic glucocorticoid, which was widely used to treat TBI, induces hypothalamic neuronal apoptosis to aggravate CIRCI. To test this hypothesis, we have evaluated the dose effect of DXM (1 or 10mg/kg) on the development of acute CIRCI in rats with fluid percussion injury-induced TBI and on cultured rat hypothalamic neurons in vitro (DXM, 10(-5)-10(-8)mol/L). Corticosterone Increase Index was recorded as the marker for CIRCI. In addition, MTT and TUNEL assays were used to measure the viability and apoptosis of hypothalamic neurons in primary culture. Moreover, high-resolution hopping probe ion conductance microscopy (HPICM) was used to monitor the DXM-induced morphological changes in neurons. The incidence of acute CIRCI was significantly higher in the high-dose DXM group on post-injury day 7. Cellular viability was significantly decreased from 12h to 24h after the treatment with a high-dose of DXM. A significantly increase in TUNEL positive cells were detected in cultured cells treated with a high-dose of DXM after 18h. Neurites of hypothalamic neuron were dramatically thinner and the numbers of dendritic beadings increased in neurons treated with the high dose of DXM for 12h. In conclusion, high-dose DXM induced hypothalamic neurons to undergo apoptosis in vivo and in vitro, which may aggravate TBI-associated CIRCI.
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Neurological Institute, 154 Anshan Road, Heping District, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, PR China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, PR China. Electronic address: clarencezhu@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhu
authors.forename: Zilong
authors.initials: Z
authors.lastname: Zhao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.forename: Hujie
authors.initials: H
authors.lastname: Lu
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000009:adverse effects*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020287:In Situ Nick-End Labeling; D008297:Male; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids
keywords: CIRCI; Glucocorticoid; HPICM; Hypothalamic neuronal apoptosis; Traumatic brain injury